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British Journal of Haematology Apr 2018Despite the significantly higher complete remission rates and improved survival achieved in the last decade, multiple myeloma (MM) patients continue to relapse due to... (Review)
Review
Despite the significantly higher complete remission rates and improved survival achieved in the last decade, multiple myeloma (MM) patients continue to relapse due to persistence of minimal residual disease (MRD). Generally, MRD refers to persistence of low levels of disease in the order of one tumour cell in ≥10 normal cells. Currently, molecular and immunophenotypic techniques are employed for MRD detection. This review focuses on MRD detection by molecular techniques, including allele-specific oligonucleotide polymerase chain reaction (ASO-PCR), next-generation sequencing (NGS) and digital PCR (dPCR), in addition to a brief description of, and comparison with, multiparameter flow cytometry. The basic principles, technical advantages and limitations, and the clinical impact of all three molecular techniques are reviewed and compared. They all have a sensitivity of at least 10 , among which ASO real-time quantitative PCR is the most well-standardized, and NGS carries the highest sensitivity and applicability, while dPCR is still under investigation. Furthermore, molecular MRD negativity is a favourable prognostic factor for survival of patients with MM. However, several challenges inherent to molecular detection of MRD still remain to be overcome, particularly false negativity and failure to detect extramedullary disease. Finally, detection of MRD from peripheral blood remains challenging.
Topics: High-Throughput Nucleotide Sequencing; Humans; Multiple Myeloma; Neoplasm, Residual; Polymerase Chain Reaction
PubMed: 29265356
DOI: 10.1111/bjh.15075 -
The Journal of Molecular Diagnostics :... Jun 2022PCR is widely used to measure minimal residual disease (MRD) in lymphoid neoplasms, but its sensitivity is limited. High Adenine/Thymine PCR and High Annealing... (Clinical Trial)
Clinical Trial
PCR is widely used to measure minimal residual disease (MRD) in lymphoid neoplasms, but its sensitivity is limited. High Adenine/Thymine PCR and High Annealing Temperature PCR (HAT-PCR) is a modified PCR designed to minimize nonspecificity and hence increase sensitivity. It was evaluated in the laboratory and the clinic, using samples from 58 patients. Of these patients, 57 were adolescents or young adults who were participating in the Australasian Leukemia and Lymphoma Group ALL06 trial in which MRD was measured in blood principally by HAT-PCR and in marrow by conventional PCR. HAT-PCR produced significantly less nonspecificity than conventional PCR, and its limit of detection was <10 in 90% of patients. In 196 samples, an excellent correlation was found between blood and marrow MRD. Variable partitioning of leukemic cells between blood and marrow was observed. Measurement of MRD in blood by HAT-PCR was noninferior to measurement of MRD in marrow by conventional PCR, in terms of both detecting disease and predicting clinical outcome. At a median follow-up of 3 years and for MRD levels in blood at the end of consolidation treatment, an MRD level of >10 cells/L significantly predicted relapse and mortality, whereas undetectable MRD significantly predicted relapse-free survival and overall survival. HAT-PCR is a simple, quick, cheap and sensitive method for measurement of MRD, and its adoption for MRD in blood may be clinically useful.
Topics: Adolescent; Bone Marrow; Humans; Neoplasm, Residual; Polymerase Chain Reaction; Recurrence; Young Adult
PubMed: 35430373
DOI: 10.1016/j.jmoldx.2022.03.007 -
BioMed Research International 2015Novel and more effective treatment strategies against multiple myeloma (MM) have significantly prolonged patients' survival and raised interest in the depth of response... (Review)
Review
Novel and more effective treatment strategies against multiple myeloma (MM) have significantly prolonged patients' survival and raised interest in the depth of response and its association with clinical outcome. Minimal residual disease (MRD) has emerged as one of the most relevant prognostic factors in MM and should be included in a new definition of complete response (CR). Although further standardization is still required, MRD monitoring should be applied in prospective clinical trials as a sensitive tool to compare and evaluate the efficacy of different treatment strategies, particularly in the consolidation and maintenance settings, and implement individualized therapy-monitoring approaches. Here, we review current definition of deep response in MM, advantages and limitations of current MRD assessment assays, clinical evidences for MRD monitoring as a prognostic tool for therapeutic decisions in MM, and challenges to develop uniform criteria for MRD monitoring.
Topics: Humans; Multiple Myeloma; Neoplasm, Residual; Prognosis; Remission Induction; Treatment Outcome
PubMed: 26783530
DOI: 10.1155/2015/832049 -
BMC Medicine May 2023The sensitivity and specificity of minimal residual disease detected by circulating tumor DNA profiling (ctDNA MRD) in lung cancer, with particular attention to the... (Meta-Analysis)
Meta-Analysis
BACKGROUND
The sensitivity and specificity of minimal residual disease detected by circulating tumor DNA profiling (ctDNA MRD) in lung cancer, with particular attention to the distinction between landmark strategy and surveillance strategy, for predicting relapse in lung cancer patients after definitive therapy has yet to be determined.
METHODS
The prognostic value of ctDNA MRD by landmark strategy and surveillance strategy was evaluated in a large cohort of patients with lung cancer who received definitive therapy using a systemic literature review and meta-analysis. Recurrence status stratified by ctDNA MRD result (positive or negative) was extracted as the clinical endpoint. We calculated the area under the summary receiver operating characteristic curves, and pooled sensitivities and specificities. Subgroup analyses were conducted based on histological type and stage of lung cancer, types of definitive therapy, and ctDNA MRD detection methods (detection technology and strategy such as tumor-informed or tumor-agnostic).
RESULTS
This systematic review and meta-analysis of 16 unique studies includes 1251 patients with lung cancer treated with definitive therapy. The specificity of ctDNA MRD in predicting recurrence is high (0.86-0.95) with moderate sensitivity (0.41-0.76), whether shortly after treatment or during the surveillance. The landmark strategy appears to be more specific but less sensitive than the surveillance strategy.
CONCLUSIONS
Our study suggests that ctDNA MRD is a relatively promising biomarker for relapse prediction among lung cancer patients after definitive therapy, with a high specificity but suboptimal sensitivity, whether in landmark strategy or surveillance strategy. Although surveillance ctDNA MRD analysis decreases specificity compared with the landmark strategy, the decrease is minimal compared to the increase in sensitivity for relapse prediction of lung cancer.
Topics: Humans; Circulating Tumor DNA; Neoplasm, Residual; Lung Neoplasms; ROC Curve; Biomarkers, Tumor; Neoplasm Recurrence, Local
PubMed: 37173789
DOI: 10.1186/s12916-023-02849-z -
Blood Reviews Jul 2017The diagnosis of acute myeloid leukemia (AML) can be made based on peripheral blood or bone marrow blasts. In this review, we will discuss the role of bone marrow... (Review)
Review
The diagnosis of acute myeloid leukemia (AML) can be made based on peripheral blood or bone marrow blasts. In this review, we will discuss the role of bone marrow evaluation and peripheral blood monitoring in the diagnosis, management, and follow up of AML patients. For patients with circulating blasts, it is reasonable to perform the necessary studies needed for diagnosis and risk stratification, including multiparametric flow cytometry, cytogenetics, and molecular analysis, on a peripheral blood specimen. The day 14 marrow is used to document hypocellularity in response to induction chemotherapy, but it is unclear if that assessment is necessary as it often does not affect immediate management. Currently, response assessments performed at count recovery for evaluation of remission and measurable residual disease rely on bone marrow sampling. For monitoring of relapse, peripheral blood evaluation may be adequate, but the sensitivity of bone marrow testing is in some cases superior. While bone marrow evaluation can certainly be avoided in particular situations, this cumbersome and uncomfortable procedure currently remains the de facto standard for response assessment.
Topics: Animals; Bone Marrow; Flow Cytometry; Humans; Leukemia, Myeloid, Acute; Magnetic Resonance Imaging; Neoplasm, Residual; Positron-Emission Tomography; Prognosis
PubMed: 28190619
DOI: 10.1016/j.blre.2017.01.003 -
Nature Reviews. Clinical Oncology Aug 2013Technological advances in the laboratory have led to substantial improvements in clinical decision making through the introduction of pretreatment prognostic risk... (Review)
Review
Technological advances in the laboratory have led to substantial improvements in clinical decision making through the introduction of pretreatment prognostic risk stratification factors in acute myeloid leukaemia (AML). Unfortunately, similar progress has not been made in treatment response criteria, with the definition of 'complete remission' in AML largely unchanged for over half a century. Several clinical trials have demonstrated that high-sensitivity measurements of residual disease burden during or after treatment can be performed, that results are predictive for clinical outcome and can be used to improve outcomes by guiding additional therapeutic intervention to patients in clinical complete remission, but at increased relapse risk. We review these recent trials, the characteristics and challenges of the modalities currently used to detect minimal residual disease (MRD), and outline opportunities to both refine detection and improve clinical use of MRD measurements. MRD measurement is already the standard of care in other myeloid malignancies, such as chronic myelogenous leukaemia and acute promyelocytic leukaemia (APL). It is our belief that response criteria for non-APL AML should be updated to include assessment for molecular complete remission and recommendations for post-consolidation surveillance should include regular monitoring for molecular relapse as standard of care.
Topics: Antineoplastic Combined Chemotherapy Protocols; Humans; Leukemia, Myeloid, Acute; Neoplasm, Residual
PubMed: 23799371
DOI: 10.1038/nrclinonc.2013.100 -
Journal of Hematology & Oncology Sep 2021Quantification of measurable residual disease (MRD) provides critical prognostic information in acute myeloid leukemia (AML). A variety of platforms exist for MRD... (Review)
Review
Quantification of measurable residual disease (MRD) provides critical prognostic information in acute myeloid leukemia (AML). A variety of platforms exist for MRD detection, varying in their sensitivity and applicability to individual patients. MRD detected by quantitative polymerase chain reaction, multiparameter flow cytometry, or next-generation sequencing has prognostic implications in various subsets of AML and at various times throughout treatment. While it is overwhelmingly evident that minute levels of remnant disease confer increased risk of relapse and shortened survival, the therapeutic implications of MRD remain less clear. The use of MRD as a guide to selecting the most optimal post-remission therapy, including hematopoietic stem cell transplant or maintenance therapy with hypomethylating agents, small molecule inhibitors, or immunotherapy is an area of active investigation. In addition, whether there are sufficient data to use MRD negativity as a surrogate endpoint in clinical trial development is controversial. In this review, we will critically examine the methods used to detect MRD, its role as a prognostic biomarker, MRD-directed therapeutics, and its potential role as a study endpoint.
Topics: Animals; Disease Management; Flow Cytometry; Hematopoietic Stem Cell Transplantation; High-Throughput Nucleotide Sequencing; Humans; Immunotherapy; Karyotyping; Leukemia, Myeloid, Acute; Neoplasm, Residual; Prognosis
PubMed: 34479626
DOI: 10.1186/s13045-021-01148-5 -
Recent Results in Cancer Research.... 2012The mechanisms driving dormancy of disseminated tumor cells (DTCs) remain largely unknown. Here, we discuss experimental evidence and theoretical frameworks that support... (Review)
Review
The mechanisms driving dormancy of disseminated tumor cells (DTCs) remain largely unknown. Here, we discuss experimental evidence and theoretical frameworks that support three potential scenarios contributing to tumor cell dormancy. The first scenario proposes that DTCs from invasive cancers activate stress signals in response to the dissemination process and/or a growth suppressive target organ microenvironment inducing dormancy. The second scenario asks whether therapy and/or micro-environmental stress conditions (e.g. hypoxia) acting on primary tumor cells carrying specific gene signatures prime new DTCs to enter dormancy in a matching target organ microenvironment that can also control the timing of DTC dormancy. The third and final scenario proposes that early dissemination contributes a population of DTCs that are unfit for immediate expansion and survive mostly in an arrested state well after primary tumor surgery, until genetic and/or epigenetic mechanisms activate their proliferation. We propose that DTC dormancy is ultimately a survival strategy that when targeted will eradicate dormant DTCs preventing metastasis. For these non-mutually exclusive scenarios we review experimental and clinical evidence in their support.
Topics: Humans; Neoplasm, Residual; Neoplasms; Tumor Microenvironment
PubMed: 22527492
DOI: 10.1007/978-3-642-28160-0_3 -
Indian Journal of Cancer 2022Neoadjuvant chemotherapy (NACT) is the standard of care for the treatment of locally advanced or non-metastatic breast cancer, which may increase the chances of breast...
Accuracy of digital mammography, ultrasound and MRI in predicting the pathological complete response and residual tumor size of breast cancer after completion of neoadjuvant chemotherapy.
BACKGROUND
Neoadjuvant chemotherapy (NACT) is the standard of care for the treatment of locally advanced or non-metastatic breast cancer, which may increase the chances of breast conservative surgery (BCS) in place of radical mastectomy without compromising on the overall survival. The aim of this study was to evaluate the accuracy of mammography (MG), ultrasound (US), and magnetic resonance imaging (MRI) in predicting the complete response and to assess the extent of residual breast cancer in women treated with NACT.
MATERIALS AND METHODS
Fifty-six consecutive patients with stage II or III breast cancer, who underwent imaging evaluation of breast with digital mammogram, US, and MRI after NACT and before the breast surgery, were included in the study. For each patient, pathologic complete response (pCR) or residual tumor (non-pCR) was predicted and the maximum extent of the residual tumor was measured on each imaging modality. These measurements were subsequently compared with the final histopathology results.
RESULTS
Of 56 patients, 22 showed pCR with MRI having better accuracy for predicting complete response than the MG and US (area under the receiver operating characteristic curve: 0.86, 0.68, and 0.65, respectively; p = 0.0001 for MRI; p = 0.06 for MG, and p = 0.02 for US). The sensitivity of MRI for detecting pCR was 72.7%; specificity and positive predictive value were 100%. For pathological residual tumor, the size measured on MRI showed significantly higher correlation with the pathologic size (correlation coefficient, r = 0.786), than the MG (r = 0.293) and US (r = 0.508) with P < 0.05.
CONCLUSIONS
Accuracy of MRI for predicting pathological complete response was significantly higher than the MG and US. Pathologic residual tumor size was also more precisely reflected by the longest tumor dimension on MRI with the strong positive correlation coefficient.
Topics: Humans; Female; Neoadjuvant Therapy; Breast Neoplasms; Neoplasm, Residual; Ultrasonography, Mammary; Mastectomy; Mammography; Magnetic Resonance Imaging; Chemotherapy, Adjuvant; Treatment Outcome
PubMed: 33753611
DOI: 10.4103/ijc.IJC_795_19 -
International Journal of Molecular... Aug 2021Neuroblastoma (NB) is a neuroectodermal embryonic cancer that originates from primordial neural crest cells, and amongst pediatric cancers with high mortality rates. NB... (Review)
Review
Neuroblastoma (NB) is a neuroectodermal embryonic cancer that originates from primordial neural crest cells, and amongst pediatric cancers with high mortality rates. NB is categorized into high-, intermediate-, and low-risk cases. A significant proportion of high-risk patients who achieve remission have a minimal residual disease (MRD) that causes relapse. Whilst there exists a myriad of advanced treatment options for NB, it is still characterized by a high relapse rate, resulting in a reduced chance of survival. Disialoganglioside (GD2) is a lipo-ganglioside containing a fatty acid derivative of sphingosine that is coupled to a monosaccharide and a sialic acid. Amongst pediatric solid tumors, NB tumor cells are known to express GD2; hence, it represents a unique antigen for subclinical NB MRD detection and analysis with implications in determining a response for treatment. This article discusses NB MRD expression and analytical assays for GD2 detection and quantification as well as computational approaches for GD2 characterization based on high-throughput image processing and genomic data analysis.
Topics: Animals; Antineoplastic Agents; Aptamers, Nucleotide; Gangliosides; Humans; Neoplasm Recurrence, Local; Neoplasm, Residual; Neuroblastoma
PubMed: 34445807
DOI: 10.3390/ijms22169101